Effect heterogeneity reveals complex pleiotropic effects of rare coding variants.

ALLSPICE detects 124 significant heterogeneous effects among 11,810 gene-trait pairs in UK Biobank RVASs of 359 traits.

• Why it matters: Understanding pleiotropy of rare coding variants is limited by existing methods designed for common variants, hindering interpretation of cross-phenotype associations.
• What they did: Researchers developed ALLSPICE, a likelihood-based R package that tests whether rare-variant effects are proportional or heterogeneous across traits, accounting for phenotypic correlation, and applied it to large-scale biobank data.
• The result: The method revealed complex effect heterogeneity within genes linked to multiple phenotypes, enhancing insights into rare-variant architectures and pleiotropy at biobank scale.